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Lifespan-extending drug given late in life reverses age-related heart disease in mice

June 12, 2013

Laboratory mice (credit: Lightmatter/Wikimedia Commons)

Elderly mice suffering from age-related heart disease saw a significant improvement in cardiac function after being treated with the FDA-approved drug rapamycin for just three months.

The research, led by a team of scientists at the Buck Institute for Research on Aging, shows how rapamycin impacts mammalian tissues, providing functional insights and possible benefits for a drug that has been shown to extend the lifespan of mice as much as 14 percent.

There are implications for human health in the research appearing in Aging Cell. Heart disease is the leading cause of death in the U.S., claiming nearly 600,000 lives per year.

Rapamycin is an immunosuppressant drug which can be used to help prevent organ rejection after transplantation. It is also included in treatment regimens for some cancers. In this study, rapamycin was added to the diets of mice that were 24 months old — the human equivalent of 70 to 75 years of age.

Similar to humans, the aged mice exhibited enlarged hearts, a general thickening of the heart wall and a reduced efficiency in the hearts ability to pump blood.

The mice were examined with ultrasound echocardiography before and after the three-month treatment period, using metrics closely paralleling those used in humans. Buck Institute faculty Simon Melov, PhD, the senior author of the study, said age-related cardiac dysfunction was either slowed or reversed in the treated mice.

“When we measured the efficiency of how the heart pumps blood, the treated mice showed a remarkable improvement from where they started. In contrast, the untreated mice saw a general decline in pumping efficiency at the end of the same three month period,” he said.

“This study provides the first evidence that age-related heart dysfunction can be improved even in late life via appropriate drug treatment,” added Melov, who said the treated mice saw a reduction in heart size, reduced stress signaling in heart tissues and a reduction in inflammation.

Buck researchers, utilizing genome analysis tools, uncovered suites of related genes which rapamycin modulates in the heart. “Rapamycin affected the expression of genes involved in calcium regulation, mitochondrial metabolism, hypertrophy and inflammation,” said Melov. “We also carried out behavioral assessments which showed the treated mice spent more time on running wheels than the mice who aged without intervention.”

“Little has been known about the functional ramifications of rapamycin in mammalian tissues,” said Buck Institute President and CEO Brian Kennedy, PhD, a co-author of the paper. “These findings are significant because we have no interest in simply extending lifespan without an accompanying improvement in the health and quality of life.”

He added, “It is particularly encouraging that, in this case, an already-approved drug that extends lifespan also improved function late in life.”

Chronic treatment with rapamycin has been problematic in both humans and mice; the drug has the potential to cause deleterious metabolic side effects including weight gain and glucose insensitivity. Melov said in this study, the drug had only mild transient metabolic effects. Future studies will focus on better understanding the molecular targets that drive age-related heart dysfunction, and why rapamycin treatment is so beneficial to the aging hearts.

This work was supported by grants from the USA National Institutes of Health and by partial support from the Larry L. Hillblom Foundation Network Grant, the Ellison Medical Foundation and the Glenn Foundation for Medical Research.

…makes you wonder why mice die so fast… why can’t we get a mouse to live to be 70 years old like humans… not just 5. With the exception of a whale, a tortoise and a few other animals it seems most animals are pre-programmed to die quite early. We do so much research on mice. It will be interesting if they one day get a mouse to live to be 50+ years…

Maybe their ability to reproduce at a young age has something to do with it? A possible consequence of this is that traits bestowing “a forted resistance ‘gainst the tooth of time” are not selected for or even outbreed.I do not know if older mice can or get to procreate though.

Perhaps -contrary to mice- humans take too long to develop for these forces to work on them and considering that we tend to reach our physical and mental peaks later, combined with the influence of accumulating experience and resources* on the survival and reproductive rates I think it likely that the median ages at which a human/ancestor animal could and was (or is) likely to create procreating offspring must be much higher than in most other species, leading to the selection of traits conducive to reaching at least that reproductive age and then some to see the developing progeny through till they can fend for themselves (pr for the most convoluted ‘sentence’).This in turn would increase their likelihood to conduct “intercourse with consequences”, preserving the responsible genes throughout time.

*(veneration of the old for their skills and experience- the archetypical elders/chieftains figures tend to have plenty of offspring, beautiful daughters and strong sons according to certain media)

” With the exception of a whale, a tortoise and a few other animals it seems most animals are pre-programmed to die quite early.”

Let’s add the elephant too.All these animals are difficult to kill (especially whales and elephants, which are large and live in herds) for most predators, except us humans, reducing their pressure to procreate early.

The big guys also need to consume much more calories, maybe this lead to adaptations in their metabolism which reduce their nutritional needs, else they might starve and die, being unable to sustain their size.A slowed-down metabolism comes to mind.Slower metabolism leads to slower aging, partly because of a reduced production of harmful metabolic products.

…your tortoise comment made me think about the race between the tortoise and the hare …with the rabbit making tons of offspring and spreading fast, but not living as long… Tortoise living very long, but not spreading as fast or mating as often. Both seem to have done well from opposite ends of the spectrum. Why would DNA not choose to have both (is the food sources abused and thus the animal wipes itself out?)

“Why would DNA not choose to have both (is the food sources abused and thus the animal wipes itself out?)”

DNA is just “a way” to store information, simply speaking.What survives its environment (including intra- and inter-species competition) stays.There may be, or have been, life-forms not based on DNA (how about RNA?).

Somewhere some ancestors of these two species, rabbits and tortoises, must have undergone mutations which spread through their respective gene pools and accumulated to result in traits that were well-suited to their respective environments.

Today this model is seen critically, but it suffices for my purpose of shedding light on this topic.

Both of these animals had to “make” certain trade-offs because of their reproductive strategies.If you want, open the link, use ctrl and f, type in example.You will see that “sea turtles” are listed as a k-selected species, and rabbits as r-selected.

The rabbit is an animal that lives in open spaces with abundant resources, and which are almost impossibly to “fill up”. Especially if you take predators into account.

Many different “forces” (e.g. competitors and things changing the environment) meet in such places, making the survival of small, overly specialized populations rather unlikely.

You can think of specialization as being gradual and having a cost adjusted to the degree you choose, while you get to only spend a limited amount of currency, which means you cannot afford to maximize both, specialization and rapid [rabbit^^] reproduction.

Over time some species get outcompeted (for resources etc) and “forced out” of their environment.Depending on geographical spread this may well mean extinction.In open spaces r-selected species predominate.

The tortoise on the other hand tends to live on isolated islands.Here, where things do not change that much, effectiveness is a given and efficiency makes all the difference, leading to highly specialized forms of live instead (due to population stabilization r-selected species cannot “outbreed” their competition, –>limited resources, more on this later).

I hope you do not mind me going a bit off-topic:
A curious parallel to this process can be seen in human culture (isolation leading to distinctiveness, specialists are distinctive too), take for example the highly developed and distinctive cultures of Britain (many parts of it are seen as ‘normal’ in ‘western culture’, but that is due to its enormous influence) and Japan.Both could be said to be more k-selected^^

The effects are not that pronounced though, since human culture can include more things easily without throwing away that much, and globalization is still shrinking the “world/environment”.This will probably lead to more “cross-pollination and finally, a more homogenous ‘world culture’, with local varieties due to substrate and mutation.Much like the many regional deviations we can observe in larger countries today.

I am not very knowledgeable in this field and I have never heard of an animal (besides us) being able to destroy its food sources completely, or long enough for extinction to occur.And even we only CAN do it, theoretically, but didn’t yet.

Some thoughts:
The biological processes involved in living, and by extension procreation, are dependent on the energy that organisms can gather from their environment, which is limited.

Since this energy is necessary for procreation, the maximum production capacity must be limited.If a population truly procreates beyond the available means, it can only temporarily do so, and the excess population would just whither away with the passage of time.If nothing else changes the population would thus find a somewhat stable equilibrium, it would stabilize .

Ps:
I have “goggled” around a bit and found this link and thought it might be of interest, since I am not good at explaining things nor qualified to give more than speculative answers (notice the characteristics part):
animals.about.com/cs/zoology/a/zoo101ae.htm

Auspicious News, more when we confront this with m-TOR bloquers actions: the expressions of the proteins- tubero sclerosis number 1 e tubero sclerosis number 2 (HAMARTIN and Tuberin) , every one SEROTONIN like. Holly cows, this for science is the milenio new . The repercussions in Cardiology (hipertrophy) and Oncology (Cancer) is awesome..
Dr.Eduardo Gonsales de ÁVILA
Cardiologist in BARRETOS-S.P=BRAZIL

…great point… I think they bump into good uses for drugs already in use for other things… (side effects turn out to be cures in some cases), or get research data from patients already taking as you point out.